Investigative Drug

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This presentation based on how will you present your case in front of ODAC meeting with FDA. It shows ability to find the data, guidances,designing of clinical trials, compilation, strategies to make …

This presentation based on how will you present your case in front of ODAC meeting with FDA. It shows ability to find the data, guidances,designing of clinical trials, compilation, strategies to make drug readily available by its ability to meet designations like fast track, priority review,orphan drug designation etc.

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  • Which guidance, rules and regulations were followed? FDA or ICH
  • The placebo matched Tarceva in shape, size, color, and packaging
  • Need a footnote
  • None of the sites were in the United States
  • Independent and Investigator Reviews of the Study
  • Reviewed by the Oncologic Drug Advisory Committee (ODAC)
  • Journal of American Medicine


  • 1. Investigative Drugpresentation toMassachusetts College of Pharmacy and Health ScienceOncologic Drugs Advisory CommitteeApril 12, 2010
  • 2. A review of Tarceva® and a proposal for anInvestigative Drugthird line monotherapy, for patients with advanced NSCLC
  • 3. Presentation preview
    • Non Small Cell Lung Cancer is a serious disease
    • 4. Patients who live beyond the first stages of the disease have few therapeutic options
    • 5. Many available therapeutic options are toxic intravenous therapies
    • 6. Tarceva® is an oral monotherapeutic option for second and third stage NSCLC
    • 7. Our investigative therapy is also a monotherapy drug for third stage NSCLC
  • Experts available for questions
    Milon Shah Lung cancer, treatment options, and the chemistry of Tarceva®Robert Fynn Tarceva® clinical trialsSandra Brown-Macioci Tarceva® approval processKristina Reinold Investigative drug proposal and clinical trial design
  • 8.
    Lung Cancer is the leading cancer killer in United States
    Leading cancer killer in men and women in United States (29% of all cancer deaths)
    219,440 new cases of lung cancer in 2009
    159,390 deaths from lung cancer
    5 year survival rate in patients with lung cancer is less than 15.2%
  • 9. Types of lung cancer
    The two main types of lung cancer are:
    Small Cell Lung Cancer (SCLC)
    about 10% of all lung cancer patients are of these type
    Non Small Cell Lung Cancer (NSCLC)
    about 80-90% of all lung cancer patients are of these type
    Other types of tumors include Lung Carcinoid Tumors, whichare slow growing and can be cured by surgery.
  • 10. Types of Non Small Cell Lung Cancer (NSCLC)
    The 3 sub-types of NSCLC differ in size, shape, and chemical composition.
    About 40% of lung cancers.
    Usually found in the outer part of the lung
    Squamous cell carcinoma: 
    About 25% to 30% of all lung cancers are this kind.
    Usually develops in the middle of the lungs, near a bronchus.
    Large-cell (undifferentiated) carcinoma: 
    About 10% to 15% of lung cancers are this type.
    It can develop in any part of the lung.
  • 11. Symptoms of NSCLC
    Persistent cough
    Trouble breathing
    Chest discomfort
    Streaks of blood in sputum
    Loss of appetite
    Inexplicable weight loss
  • 12. How is NSCLC diagnosed?
    Physical exams
    Laboratory tests
    Chest x-ray
    CT scan
    PET scan
    Sputum Cytology
    Fine-needle Aspiration (FNA)
  • 13. Stages of NSCLC
    Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.
    Stage 0
  • 14. Stages of NSCLC
    Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.
    Stage 0
    Stage IA & IB
  • 15. Stages of NSCLC
    Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.
    Stage 0
    Stage IA & IB
    Stage IIA & IIB
  • 16. Stages of NSCLC
    Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.
    Stage 0
    Stage IA & IB
    Stage IIA & IIB
    Stage IIIA & IIIB
  • 17. Stages of NSCLC
    Based on severity of Lung Cancer, it is assigned by different stages. Staging will help determine whether cancer has spread within lungs or in the other parts of the body.
    Stage 0
    Stage IA & IB
    Stage IIA & IIB
    Stage IIIA & IIIB
    Stage IV
  • 18. Treatment Approaches for NSCLC
    Radiation Therapy
    Targeted Therapy
    Laser Therapy
    Photodynamic Therapy
  • 19. Drug approved for NSCLC treatment
    Alitma® (pemetrexed)
    Avastin® (bevacizumab)
    Gemzar® (gemcitabine)
    Iressa® (gefitinib)
    Photofrin® (porfimer)
    Taxol® (paclitaxel)
    Tarceva® (erlotinib)
  • 20. Tarceva® (erlotinib) – the first EGFR oral targeted agent for NSCLC ir_update/inv-update-2008-11-14.htm
  • 21. Tarceva® indication
    Tarceva® is prescribed for patients with advanced-stage non-small cell lung cancer (NSCLC) who have received at least one prior chemotherapy regimen
  • 22. Mechanism of Action of Tarceva®
    Pharmacology Category :
    Human Epidermal Growth Factor Receptor Type 1/ Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor
    Inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR).
  • 23. Chemistry of Tarceva®
    Active ingredient:
    Erlotinib hydrochloride
    Chemical Name:
    Chemical Structure
  • 24. Tarceva® Clinical Trials
    Phase II Trial
    Study A248-1007
    Phase III Trials
    • Study BR.21
    • 25. The Saturn Study
  • Phase II Clinical Trial assessed efficacy and safety of Tarceva®
    Study A248-1007
    A multicenter, open-label, single arm trial
    57 patients received 150mg tablet/day following the failure of platinum based combination chemotherapy
    Assessed the efficacy and safety of Tarceva® in patients with Stage IIIB or IV, EGFR positive NSCLC
  • 26. Phase II Clinical Trial treatment and population
    Treatment was taken until disease progression or unmanageable toxicity
    Median age of the study was 62 years, with 74% of the patients historically smokers
    60% of patients were females and 91% were Caucasian
  • 27. Phase II Clinical Trial showed improved response rates
    2 of the patients had complete response (CR)
    5 had partial response (PR)
    The objective response rate was 12.3% (95% CI:5.1-23.7 %)
    The median overall survival was 8.4 months (95% CI:4.8-13.9 months)
  • 28. Phase III Clinical Trial Study BR.21
    Multicenter, international, randomized, placebo-controlled, double blinded clinical study
    Designed to compare Tarceva® to a placebo
    Enrolled 731 patients
    Conducted in 86 study centers in 17 countries
    Sites locations included:
    1 in USA
    27 in Canada
    58 (rest of the world)
  • 29. Study BR.21 requirements
    Patients ≥ 18 years old with histologically or cytologically confirmed diagnosis of incurable Stage IIIB or IV NSCLC
    Received one but no more than two prior treatment (one of the treatment had to be a combination of chemotherapy)
    Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3
    Adequate renal and hepatic functions
  • 30. BR.21 trial process
    • Dose self-administered in the morning with up to 200ml of water an hour or two after ingestion of food or medications
    • 31. Increase in dosage not permitted
    • 32. Treatment continued until progression of disease or intolerable toxicity
  • 33. The objective endpoint of the study was to compare the Overall Survival (OS) between the two study arm (Tarceva® vs. Placebo)
    Secondary endpoints included:
    Progression-free-survival (PFS)
    Response Rate
    Response Duration
    Quality of life (QoL)
    OS was BR.21 trial primary endpoint
  • 34. Tarceva® reduced the risk of death by 27%
    Efficacy was evaluated by:
    Periodic assessments of survival and quality of life (QoL) scores
    Tumor measurement evaluated every 8 weeks
    Safety assessed in every 4 weeks
  • 35. Tarceva® efficacy results
    Eastern Cooperative Oncology Group (ECOG)
  • 36. Tarceva® response rate on patients with positive EGFR
    Evaluation of positive epidermal growth factor receptor (EGFR) (defined as 10% of cells sustaining for EGFR) and negative EGFR
    Status was determined in 33% patients (238)
    Tarceva® response rate on positive EGFR was 12% and 3% on negative EGFR
  • 37. Saturn Study evaluated the effect of EGFR protein and clinical outcome
    A post marketing Phase III study to evaluate the relationship between EGFR protein expression and clinical outcome:
    Compared Tarceva® and Placebo as maintenance treatment of patients with locally advanced or metastatic NSCLC following 4 cycles of platinum based chemotherapy
    889 patients enrolled in a global, multicenter, randomized, double blinded, placebo-controlled study
  • 38. Saturn divided into 2 study periods
    The chemotherapy run period
    Patients received first line platinum based doublet chemotherapy
    The study period
    Patients received blinded Tarceva® or Placebo
    438 patients received Tarceva ™
    451 patients received a placebo
  • 39. Saturn study requirements
    Patients with locally advanced Stage IIIB or metastatic (Stage IV) NSCLC
    Submission of formalin-fixed, paraffin-embedded tumor tissue samples within 3 weeks of starting chemotherapy
    ECOG performance status of 0-1 before and after chemotherapy
    Adequate hematopoietic and end-organ function
  • 40. PFS was Saturn study primary endpoint
    The primary objective endpoint for the study was progression-free-survival (PFS) —comparing Tarceva® to Placebo
    Secondary endpoint was Overall Survival (OS)
  • 41. Saturn study met primary endpoint
    Demonstrated a significant improvement in assessed PFS in the overall population and with EGFR IHC-positive tumors
    PFS Improvements
    41% in overall population
    45% in EGFR IHC-positive population
    Median PFS was 11.1 weeks in the placebo arm vs. 12.3 weeks in the Tarceva® arm
  • 42. Saturn study time to event results
  • 43. Most adverse events associated with Tarceva® include rash and diarrhea, which are manageable
    Tarceva® safety concerns
  • 44. A well tolerated, oral agent to maintain tumor regression from chemotherapy and to prolong time to progression for patients with NSCLC
    Alternative to intravenous maintenance therapy with a high toxicity profile
    Tarceva® provides an unmet medical need
  • 45. Tarceva® approval process
  • 46. Tarceva® qualifies for Fast Track status
    For use with a serious disease non small cell lung cancer (NSCLC)
    Positively impacts survival, quality of life
    Inhibits disease progression
    Fills an unmet medical need by showing superior effectiveness to available therapies
    First EGFR oral targeted agent for NSCLC ir_update/inv-update-2008-11-14.htm
  • 47. Tarceva® qualifies for a Rolling Review
    Fast Track status
    Select group of innovative therapies
    FDA began reviewing Tarceva®components in January 2004 and ended in July 2004, “OSI, Genentech, Roche begin filing Tarceva rolling NDA”, BioWorld Week January 26, 2004
  • 48. Tarceva® qualifies for Priority Review
    • Fast Track status
    • 49. Significant treatment advancement
    • 50. Initial submission
  • 51. From FDA on November 18, 2004 for treatment of NSCLC after failure of at least 1 chemotherapy regimen
    Tarceva® approved under the Pilot Program for Continuous Marketing Applications
    Tarceva® demonstrated an increase in overall survival in advanced NSCLC patients
    Tarceva® receives approval
  • 52. Tarceva® application accepted for an sNDA
    On June 15, 2009, as a first-line maintenance therapy for patients with locally advanced or metastatic NSCLC
    Acceptance based on double-blind trial, SATURN
    Delivers effectiveness comparable to chemotherapy
    Significantly improves QOL without the toxic side effects of chemotherapy such as nausea and vomiting ir_update/inv-update-2008-11-14.htm
  • 53. Tarceva® reviewed by ODAC
    Oncologic Drugs Advisory Committee (ODAC) voted against recommending Tarceva® as a “switch” maintenance therapy
    FDA extended the review action on the sNDA to April 18, 2010
  • 54. Investigative Drug
    • Multi-Tyrosine Kinase Inhibitor
    • 55. Inhibits tumor growth and blood supply
    • 56. Oral monotherapy 3-23-10
  • 57. Investigative Drug: Proposed Indication
    Third line therapy for advanced NSCLC
    Patients must have been previously treated with 2 prior chemotherapeutic agents
    Tarceva® is currently the only approved drug for third line therapy 3-23-10
  • 58. Who makes it to third line therapy?
    • Controversy regarding purpose of third-line therapy
    • 59. Study done by Dr. Nicholas Girardi at Centre Hospitalier Universitaire de Besançon in France between 2000-2006
    • 60. 613 patients received first line chemotherapy for advanced NSCLC
    • 61. 173 (28%) went on to receive both second and third line therapy 3-15-10
  • 62. Center for Drug Evaluation & Research (CDER)
    Office of Oncology Drug Products (OODP)
    Director: Richard Pazdur, MD
    Associate for Director of Regulatory Affairs:
    Glen Jones, Ph. D
    Division of Drug Oncology Products (DDOP)
    Director: Robert Justice, MD
    Deputy Director: Ann Farrell, MD April 2010
  • 63. CDER Approval Statistics
    26 new drugs in 2009
    7 biologics
    5 priority review 4-5-10
  • 64. OODP Statistics
    9 total oncology drugs in 2009
    3 Accelerated Approval
    53 oncology indications approved from July 2005 – December 2007
    60 applications in total reviewed
    18 indications for new drugs
    35 indications for previously approved drugs
    9 drugs received accelerated approval
    25% of 53 new indications based on overall survival 4-4-10
  • 65. Oncologic Drugs Advisory Committee (ODAC)
    13 voters
    One non-voter
    General, pediatric, hematologic, immunologic and several other oncology specialties represented
    L.T. Nicole Vesely, Pharm. D., R.Ph., Desingated Federal Official 4-4-10
  • 66. Previous ODAC meetings
    March 2003 meeting with Astra Zeneca regarding Iressa™
    Confirmatory trial fails to support initial accelerated approval
    December 2009 meeting with OSI Pharmaceuticals, Inc. regarding Tarceva®
    Inclusion of EGFR-negative population
    “Switch Maintenance Therapy” rejected
  • 67. 3-20-10
  • 68. Stratification
    • EGFR mutations
    More likely to occur in:
    Asian race
    Patients with adenocarcinoma
    • Prior use of tyrosine kinase inhibitors 3-23-10 3-25-10
  • 69. Phase I: Safety
    • Confirming less toxicity than chemotherapy
    • 70. Focus on dosing
    • 71. Major focus on hematological effect on patients
    • 72. All regimens continue until disease has progressed or severe toxicity has presented 3-23-10
  • 73. Phase II: Safety and Efficacy
    Primary endpoint: Overall Objective Response Rate (Partial and Complete Responses)
    Shown to be that of 13.1%
    8 month duration of response
    Improvement over Tarceva
    Secondary endpoints: Progression-Free Survival (PFS), Overall Survival (OS)
    Of 250 participants two Grade 5 events due to internal hemorrhage 3-23-10 3-25-10
  • 74. Phase III: Risk vs. Benefit
    • Confirmatory Trial for full approval
    • 75. Investigative Drug vs. Tarceva®
    • 76. Randomized double-blinded study in 1,200 patients
    • 77. Improved overall survival 3-23-10 3-25-10
  • 78. Designations
    Orphan Status?
    NSCLC affects more than 200,000 people per year
    Fast Track?
    Third line therapy for Stage IIIB and IV NSCLC
    Provides unmet medical need for patients with serious life-threatening condition
    Applied for Fast Track designation in Phase I
    T. Class, In-Class Lecture, 1-11-10
  • 79. Investigative Drug Approval Process
    With fast track designation, priority review and accelerated approval may be offered
    Priority Review? Has improved objective response rate over Tarceva®
    Accelerated Approval? Surrogate endpoint of objective response rate in phase II trial reasonably predicts clinical benefit along with 8 month duration of response
    T. Class, In-Class Lecture, 1-11-10
  • 80. Conclusion
    Investigative drug provides:
    • An unmet need
    • 81. Monotherapy
    • 82. Improved quality of life for patients with third stage NSCLC
    • 83. Alternative therapy to Tarceva®, which most benefits EGFR positive patients
  • Who was the director FDA when Tarceva® was granted Fast Track Status?
    Richard Padzur
  • 84. How many drugs were granted Fast Track status the same year as Tarceva® ?
  • 85. Was Tarceva® granted orphan status?
    Greater than 200,000 people are diagnosed with NSCLC each year in the US
  • 86. ECOG performance status
    The Eastern Cooperative Oncology Group (ECOG) is one of the largest clinical cancer research organizations in the United States, and conducts clinical trials in all types of adult cancers.
  • 87. Considerations for Future
    Trials conducted in Asian population in Asian countries vs. Asian population in the U.S.
    Lower smoking rate in Asian countries than U.S.
  • 88. What is a nonsmoker?
    A never-smoker is defined as under 100 cigarettes within life 3-30-10
  • 89. Pediatric Population
    Because advanced NSCLC has not shown to affect the pediatric population FDA can waive the requirement to test our investigative drug in children
  • 90. Confidence Interval
    Expected range of outcome: a range of statistical values within which a result is expected to fall with a specific probability
    Encarta® World English Dictionary[North American Edition] © & (P) 2009 Microsoft Corporation.All rights reserved. Developed for Microsoft by Bloomsbury Publishing Plc.
  • 91. Hazard Ratio
    How often a particular event happens in one group compare to how often it happens in another group, over time. In cancer clinical trials it measures survival at any point in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less means that survival was better in one of the groups.